Individualised biological treatment in rheumatoid arthritis

182 Pages·2014·1.83 MB·Dutch

Individualised biological treatment in rheumatoid arthritis
Noortje van Herwaarden
Cover design, layout and printing: Off Page, Amsterdam
www.offpage.nl
Cover picture: Shutterstock.com
ISBN: 978-94-6182-521-6
Copyright © 2014 by Noortje van Herwaarden
Individualised biological treatment in rheumatoid arthritis
Geïndividualiseerde biological behandeling bij reumatoïde artritis
(met een samenvatting in het Nederlands)
Proefschrift
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de
rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het
college voor promoties in het openbaar te verdedigen op dinsdag 27 januari 2015
des middags te 4.15 uur
door
Noortje van Herwaarden
geboren op 10 april 1985
te Nijmegen
Promotoren: Prof. dr. J.W.J. Bijlsma
Prof. dr. R.F. van Vollenhoven
Copromotoren: Dr. A. van der Maas
Dr. B.J.F. van den Bemt
contents
Chapter 1 General introduction 7
Chapter 2 Can response duration after the first rituximab treatment be
used in timing of rituximab retreatment? 19
Chapter 3 Dose reduction of tocilizumab in rheumatoid arthritis patients
with low disease activity 25
Chapter 4 Down-titration and discontinuation strategies of tumor necrosis
factor-blocking agents for rheumatoid arthritis in patients with
low disease activity 37
Chapter 5 Dose REduction Strategy of Subcutaneous TNF inhibitors in
rheumatoid arthritis: design of a pragmatic randomised non-
inferiority trial, the DRESS study 95
Chapter 6 Randomised controlled non-inferiority study of disease activity
guided dose reduction and withdrawal of adalimumab and
etanercept compared to usual care in rheumatoid arthritis 113
Chapter 7 Prediction of successful dose reduction or discontinuation
of adalimumab or etanercept using serum drug levels and
antidrug antibody measurement 133
Chapter 8 Summary and general discussion 145
Chapter 9 Nederlandse samenvatting 161
List of publications 169
Curriculum Vitae 173
Dankwoord 177
5

o n e
General introduction

RHeUMAtoID ARtHRItIs
1
Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown aetiology.
The prevalence is between 0.5% and 1% of the adult population. It affects women
G
about three times more often than men. The onset of the disease is mostly between e
n
e
the fourth and sixth decade of life.1, 2 RA is characterised by inflammation of synovial r
a
l
joints, most often of the small joints of hands and feet. This leads to pain, stiffness, in
t
swelling and subsequent limited function. The inflammation can cause damage to r
o
cartilage and bone.3 Also, systemic manifestations can occur, including for example, du
c
skin vasculitis and pulmonary nodules or interstitial fibrosis.2 The main goal of t
io
treatment is to reduce pain and swelling, prevent joint destruction and maintain n
physical, social and emotional functioning.
PHARMAcoLoGIcAL tReAtMent oF RHeUMAtoID ARtHRItIs
The pharmacological treatment options for RA have grown steadily the past
decades. In the past a limited number of drugs was available including Non-Steroidal
Anti Inflammatory Drugs (NSAIDs), conventional synthetic Disease Modifying Anti
Rheumatic Drugs (csDMARDs) and glucocorticoids. Whereas NSAIDs only relieve
symptoms like pain and stiffness, csDMARDs (like among others methotrexate,
sulfasalazine, leflunomide and hydroxychloroquine) and glucocorticoids also
influence the natural course of RA.4
Due to a better understanding of the pathogenesis of the disease, development
of a new group of biological DMARDs (bDMARDs) was possible. These biologic
agents target different cells (B- and T-cells) and cytokines (tumor necrosis factor
(TNF), interleukin 6 (IL-6)) involved in the inflammatory cascade. Anti-Tumor Necrosis
Factor (TNF) agents are a subgroup of these biologic agents. The most widely
used anti-TNF agents in rheumatoid arthritis are adalimumab, a human anti-TNF
monoclonal antibody against human TNF-α, and etanercept, a human TNF receptor
fusion protein. Other anti-TNF agents include certolizumab pegol, infliximab and
golimumab. They all have proven to be effective in improving, clinical, functional
and radiographic outcomes in patients with RA.5-9 Other bDMARDs that have
demonstrated their effectiveness in RA treatment include rituximab, a chimeric
monoclonal antibody against CD20 positive B-cells10, tocilizumab, a humanised anti-
Interleukin-6 (IL-6) receptor antibody against human IL-6-receptor11 and abatacept,
a soluble recombinant fusion protein inhibiting T-cell activation.12
With these different treatment options, the current goal in treating RA is to
achieve and sustain low disease activity or even remission. To reach that goal,
treatment is initiated early in the disease and patients are treated with a combination
of different drugs to reach low disease activity as soon as possible.13, 14 Additionally,
a tight control strategy or “treat-to-target”, which consists of regular measurement
of disease activity and making treatment adjustments to reach a predefined target
9
(usually low disease activity or remission), has been shown to improve clinical,
1
functional and radiographic outcomes compared with routine outpatient care.15, 16
G InDIVIDUALIseD tReAtMent
e
n
e
r Biological DMARDs have a few drawbacks. One is a modest, in part dose dependant,
a
l
in increased risk of adverse effects, mostly of (serious) infections and skin cancer.17-20
t
r Another important drawback is the high costs of the bDMARDs, compared to the
o
d
u csDMARDs.21 Therefore optimal dosing of these drugs is warranted by use of these
c
tio drugs in the right patients, using the lowest effective dose/longest effective interval
n and stopping the drug when possible, to achieve optimal effect and minimise
adverse effects and costs. The different bDMARDs available for RA have their own
pharmacological characteristics and subsequently need different strategies to reach
the lowest effective dose. This thesis will therefore discuss several dosing strategies
for rituximab, tocilizumab and anti-TNF agents.
Rituximab
Rituximab is given in RA patients intravenously using two induction infusions two
weeks apart. Treatment thereafter is discretionary. Optimal dosing/scheduling
of rituximab is therefore different compared to the other bDMARDs, as it is not
registered in a fixed treatment schedule. Although the registered dose of rituximab
is 2 x 1000 mg, results from the randomised pivotal trials support that 2x 500 mg is
equivalent for all major outcomes.22
This thesis focuses however not on the dose, but on the retreatment schedule of
rituximab. Retreatment is advised after at least 16 weeks.23 Duration of response to
rituximab differs between patients, with most patients needing retreatment within
6 to 12 months.24-26 This large inter-individual variability in duration of response
makes it difficult to optimally time retreatment. Different treatment strategies are
being used in clinical practice, including 1) on demand retreatment, with retreatment
in case of increase in disease activity, 2) treat-to-target, with retreatment when a
predefined target is met, and 3) fixed retreatment, with retreatment for example
every 6 months.22 However, the optimal rituximab treatment strategy for the
individual patient has yet to be determined.
Tocilizumab
The registered dose of tocilizumab is 8mg/kg intravenously every 4 weeks in Europe.23
Only a few small studies on tocilizumab dose reduction or discontinuation are
available at this point. With respect to discontinuation, a tocilizumab discontinuation
study showed 35.1% and 13.4% of patients still in low disease activity 24 and 52
weeks after tocilizumab discontinuation, respectively.27 Another small study with
patients who discontinued tocilizumab showed 45.7% of patients still in low disease
activity after 52 weeks.28 In the ACT-RAY study, 86% of patients experienced flare in
10